Methylacetylenic putrescine (MAP), an inhibitor of polyamine biosynthesis, prevents the development of collagen-induced arthritis.
The objective of the present investigation was to examine the effects of an irreversible inhibitor of ornithine decarboxylase (2R,5R)-6-heptyne-2,5,diamine (methylacetylenic putrescine, MAP) on experimentally induced arthritis in mice. MAP (0.5-0.05%) was administered in drinking water to DBA/1 mice immunized with native chick type II collagen (CII). The development of arthritis was inhibited only in those mice receiving 0.5% MAP; lower doses were ineffective. Putrescine and spermidine levels were decreased and spermine levels were increased in spleen and lymph node cells from drug-treated mice compared to control arthritic mice. Furthermore, when control mice were developing arthritis, serum anti-CII antibody levels were lower in the MAP-treated group. MAP inhibited antibody production early in the immune response to CII; there was an association between inhibition of antibody production and inhibition of the development of arthritis. When MAP was discontinued, the nonarthritic, drug-treated mice did not develop the disease. Late administration of MAP (beginning 19 days after CII immunization) did not affect the incidence or the severity of the arthritis. Cyclophosphamide treatment begun at the same time significantly inhibited the development of the disease. In vitro T cell responses to denatured type II collagen (dCII) in untreated and MAP-treated mice were examined 14 days after immunization with CII. This is a time of peak T cell responsiveness in untreated animals. MAP treatment had no effect on the T cell response to dCII. These results indicate that MAP can prevent the development of CII-induced arthritis, possibly by inhibiting the autoantibody response. Therefore, inhibitors of polyamine biosynthesis deserve further investigation as potential immunosuppressive agents.
Wolos
J A
JA
Department of Cell Biology, Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Logan
D E
DE
Bowlin
T L
TL
D000480:Alkynes; D000818:Animals; D001168:Arthritis / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000517:prevention & control*; D015317:Biogenic Polyamines / Q000032:analysis; D003094:Collagen / Q000276:immunology*; D003959:Diamines; D007114:Immunization; D007074:Immunoglobulin G / Q000032:analysis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D065108:Ornithine Decarboxylase Inhibitors; D011700:Putrescine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology
D000480:Alkynes; D015317:Biogenic Polyamines; D003959:Diamines; D007074:Immunoglobulin G; D065108:Ornithine Decarboxylase Inhibitors; C039613:6-heptyne-2,5-diamine; D003094:Collagen; D011700:Putrescine